Abstract

Introduction

Interleukin-34 (IL-34) is a recently defined cytokine, showing a functional overlap
with macrophage colony stimulating factor (M-CSF). This study was undertaken to address
the expression of IL-34 in rheumatoid arthritis (RA) patients and to investigate its
regulation and pathogenic role in RA.

Methods

IL-34 levels were determined in the RA synovium, synovial fluid (SF) and fibroblast-like
synovial cells (FLS) by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent
assay and immunoblotting. RA activity was assessed using Disease Activity Score 28
(DAS28) activity in the plasma collected at baseline and one year after treatment.
Conditioned media (CM) were prepared from RA FLS culture with tumor necrosis factor
alpha (TNFα) for 24 hours and used for functional assay.

Results

IL-34 was expressed in the synovium, SF, and FLS from RA patients. The production
of IL-34 in FLS was up-regulated by TNFα in RA samples compared with osteoarthritis
(OA) patients. Importantly, the preferential induction of IL-34 rather than M-CSF
by TNFα in RAFLS was mediated by the transcription factor nuclear factor kappa B (NF-κB)
and activation of c-Jun N-terminal kinase (JNK). IL-34 elevation in plasma from RA
patients was decreased after the administration of disease-modifying anti-rheumatic
drugs (DMARDs) in accordance with a decrease in DAS28. CM from RAFLS cultured with
TNFα promoted chemotactic migration of human peripheral blood mononuclear cells (PBMCs)
and subsequent osteoclast (OC) formation, effects that were attenuated by an anti-IL-34
antibody.

Conclusions

These data provide novel information about the production of IL-34 in RA FLS and indicate
that IL-34 is an additional osteoclastogenic factor regulated by TNFα in RA, suggesting
a discrete role of IL-34 in inflammatory RA diseases.